Process of preparing derivatives of 21-hydroxy-pregnene-(5)-ol-(3)-one-(20)



Patented May 22, 1951 UNITED STATES PATENT OF FI CE? PROCESS OF PREPARING DERIYATIYESOF 21 HYDROXY PREGNENE (5) -0L (3')- ONE-(20,)

Heinrich Ruschig, Frankfort-on-tlie-Main-,- Ger-'- many, assignor to. Farbwerke Hoechstwormals: Meister Lucius, & Bruning; Frankfort-on.-.-the.-.-. Main-Hoechst; Germany,

No Drawing. Application April'Z'T, 1949, Serial. No. 90,037. In Germany March 18, 1949' 3 Claims. (Cl. 2 60.3-9-v7.4),

The present invention relates to a process of preparing derivatives of 2l-hydroxy-pregene-( 5) 01(3) -one-(20).

The French Patent No. 8,9-li44l describes the manufacture of derivatives of Zl-hydroxy-pregnene-(5)-ol-(3)-one-(20) which consists in treating pregnene (5)-ol- (3)'-one-(20)-oxalic acid-(21)" in the form of its-water-soluble salts ofithe'formula,

. CH; CH3.

Me: alkali .metal omewith iodine and a basic agent and causing the 21- iodo pregnene (5) ol (3) -one;-(20) obtained which has the formula to react with a; salt of an organic acid or another compound'capable of' replacing the iodine.

Now I have found that the derivatives of 21- hydroxy-pregnene- (5) -o1-(3 -one-(20) are obtained in a technically simple manner and in good 3 yield by iodinating already the enol-alkali salt of the pregnene-(5)-ol-(3)0ne (2,0) oxalic ester-(21) corresponding to the formula:

CH3 CH3 OMeY- R: alkyl Meza-lka-lbmetal- The process is, for instance, carried out as follows: the enol-sodium or potassium salt of a pregnene- (5) -ol-(3) -one- (20) -oxalic acid ester- (21), for instance the methyl-, ethyl-, propyl-, butyl': or-amyl-ester of the 'formulaas-referred' to above is'suspendedin methyl-, ethylor propyl= 7 alcohol and the calculated quantity: oiiodineadis: solved in-methy-b, ethylor propyl-alcohol is-then caused to 110W in at a temperature :of from about -30*C. to 0. During thisoperation. the.- 2 1- iOdo-pregnene-(Sl -ol- (3) -one--(20,)' -oxalic-: ester.-

(21 lot the formula:

CH3 CH3 iii 0 (lJ--(Er-'( ;C 0.0 R, 10 I is formed as an intermediate product; this being evident: bythegradual transformation oi the sus pension into a clear solution. The solution assumes a brown-red color. When theaddition of iodine is complete, the solution. isepouredinto a strongly dilute aqueous alkaline solution which, moreover, contains an electrolyte, for instance, a solution of sodium chloride or phosphate. By stirring for several. hours the acid cleavageinto 2l-iodo-pregnene- (i5) -ol (3s).-one-tof the for: mulav OH; a CH, 0

U-E-cHio-ti-R Rzzalkylby-exchang-ingthe halogen for the acid radical of salts of carboxylic acids inasolvent miscible The following example serves to illustrate th invention, but it is not intended to limit it 1 i thereto: 7 H v p 4.38 grams /1oo mol) of thesodiumsalt of pregnene- -0l- (3) -one- (20) -oxalic' acid ethyl ester-(21) are suspended in 50 cc. of methanol; a

solution of 2.54 grams of iodine in 60 cc, of methanol is caused to run withinminutes at a temperature of C., while stirring,'.into :1

that mixture. The suspension gradually turns into a red-brown solution, the temperature rises up to 10 C. The whole is further stirred for'30 minutes and the reaction solution is poured into 1100 cc. of water containing 100 cc. of a saturated sodium chloride solution and 2 grams of potassium hydroxide. .The mixture is then'stirred-for '16 hours in the dark whereupon the crude 21- iodo-pregnene- (5) -ol- (3) -onewhich has separated in the form of flakes is filteredby suction'oncentrifuged. It is dissolved in 350 00,01; methanol and carefully precipitated with 100120. of water. It is allowed to stand for 24 hours, centrifuged, washed with methanol of 20 per cent strength and dri'ed 'inthevacuum at 56 C.

The yield amounts to 3.2 grams, the melting point is at 155-156 C. (uncorrected)with decomposition.

The crude zl-iodo-pregnene- (5) -ol- (3) -one- (20) may also be processed directly without any further purification. 7

3.2 grams of V 2 l-iodo-pregjnene-(5) -ol- (3) mic- 220, cc. of acetone I I 4 3 grams of potassiumacetate 55 cc, of water, and; 2.500 of glacial acetic acid are boiled for 5 hours under reflux, the reaction solution is then' 'evaporated in the vacuum and the white residue is absorbed with acetic *ac'id ethyl ester and water! The acetic ester solution is washed ;with.sodium-=bisulfite and water and finally dried over sodium: sulfate. After the evaporation is com'plete a whiteresidue remains which contains the 21"-acetoXypregnene-(5) -ol- (3) -one-(20). By a crystallization from aqueous and pure acetone it is ob-tainedin the-pure state. The yield amounts to 2.1 grams, the melting point is at 179 C. 1 Iclaim: 1.'A process for producing 21-hydroxy1pregheme-(5), ol -.(3).- one (20) derivatives which comprises iodinating in the absence of watera pregnene-(5)'-'01-'(3)-one-(20)-oxalic ester (21) inthe form of .an enolalkali salt of the' formula jecting the thus formed 21-iodo-pre nene-(5)- ol-(3) -one-(20) -oxalic ester-(21) of the formula CH3 O to an acid cleavage in an alkaline medium and Irv reacting the thus formed 21-iodo-pregnene-(5)- f ol-(3)-one-(20) 'ofthe formula CH3 CH;

CH5 CH3 OMe wherein Me stands for an alkali metal and R for an alkyl radical, in a water-miscible solvent at a temperature of from about C. to 0 C., subjecting the thus formed 2 1-iodo-pregnene- (5) -ol-(3) -one- (20) foxalic ester-(21) of the Q formula 9 to an acid cleavage in an alkaline medium and reacting the thus formed 21-iodo-pregnene-(5) ol-(3) -one-(20) of the formula CH3 CE;

6 vii;

CH ONa /\'JE CH= E C 0.00%

in a water-miscible solvent at a temperature of from about -30 C. to 0 (3., subjecting the thus formed 2l-iodo-pregnene-(5) -01 (3) one-(20- oxalic acid ethyl ester to an acid cleavage in an alkalaline medium and reacting the thus formed 21-iodo-pregnene-(5) -o1-(3) -one-(20) of the formula:

on,5 CH3 AUX-01121 with an alkali acetate in a water-miscible solvent at neutral to weakly acid reaction.

HEINRICH RUSCHIG.

REFERENCES CITED The following references are of record in the file of this patent:

FOREIGN PATENTS Country Date France Dec. 11, 1943 Number 

1. A PROCESS FOR PRODUCING 21-HYDROXY-PREGNENE-(5)-01-(3)-ONE-(20) DERIVATIVES WHICH COMPRISES IODINATING IN THE ABSENCE OF WATER A PREGNENE-(5)-01-(3)-ONE-(20)-OXALIC ESTER-(21) IN THE FORM OF AN ENOL ALKALI SLAT OF THE FORMULA 